Analysis of FDC-P2, BaF3, and 32Dc123 cells infected with a drug-selectable retroviral construct (ME26neo) expressing the avian leukemia virus E26-derived gag-myb-ets fusion oncogene demonstrated that drug-resistant infected cells acquire the capacity to grow on erythropoietin (EPO) in place of IL-3, and increased expression of RNA specific for the erythroid transcription factor GATA-1, the erythropoietin receptor (EpoR) and beta-globin requires exposure to EPO for at least 48 hours (GATA-1 and EpoR) and 3-5 days (beta-globin). Expression of the fusion oncogene blocked apoptosis in FDC-P2 cells shifted from IL-3 to EPO, while control and vector-infected cells showed significant apoptosis within 6 hours of a shift to EPO and were 100% nonviable within 48 hours. In contrast, ME26neo-infected FDC-P1 cells became factor-independent, and began to express IL-3 following a shift to factor-free media. Factor-independent, ME26neo- infected FDC-P1 cells were tumorigenic in nude mice, and tumors were characterized as early-stage myelocytic or promyelocytic. Analysis of several human cell lines indicated that HEL and K562 cells showed increased expression of ETS1, but not ETS2, ERG-B/FLI-1, or PEA3 when they were induced to differentiate along an erythroid pathway. Cells infected with an ETS1 retroviral expression construct expressed significantly increased expression of erythroid markers, such as hemoglobin and glycophorin A, and exhibited an increased sensitivity to erythroid-specific inducers, such as cytosine arabinoside, but not the monocyte/macrophage-inducing phorbol ester, 12-0-tetradecauoylphorbol- 13-acetate.